The transient receptor potential vanilloid-1 (TRPV1) is a capsaicin-responsive ligand-gated cation channel selectively expressed on small, unmyelinated peripheral nerve fibers (cutaneous nociceptors). See Caterina and Julius, 2001, “The vanilloid receptor: a molecular gateway to the pain pathway,” Annu Rev Neurosci. 24:487-517; and Montell et al., 2002, “A unified nomenclature for the superfamily of TRP cation channels,” Mol. Cell. 9:229-31. When TRPV1 is activated by agonists such as capsaicin and other factors such as heat and acidosis, calcium enters the cell and pain signals are initiated. After disease or injury, cutaneous nociceptors may become persistently hyperactive, spontaneously transmitting excessive pain signals to the spinal cord in the absence of painful stimuli, resulting in various types of chronic pain. When TRPV1 is continuously activated through prolonged exposure to an agonist (e.g., capsaicin), excessive calcium enters the nerve fiber, initiating processes that result in long-term yet reversible impairment of nociceptor function. This is believed to be the mechanism by which application of capsaicin provides relief from pain.
Capsaicin may be effective for amelioration of conditions or diseases other than pain, as well. For example, capsaicin acts as an anti-inflammatory agent, counter-irritant, antipruritic, anti-psoriatic and anti-itch agent (for review, see Szallasi and Blumberg, 1999, “Vanilloid (Capsaicin) Receptors and Mechanisms,” Pharm Revs, 51:159-211). In addition, capsaicin has been reported to cause apoptosis and/or inhibit proliferation of malignant cancer cells (for review, see Surh, 2002, “More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide,” J Nat Cancer Inst, 94:1263-65), and to reduce sinonasal polyps (Baudoin et al., 2000, “Capsaicin significantly reduces sinonasal polyps” Acta Otolaryngol 120:307-11).
Low-concentration capsaicin creams have been used for years to treat painful neuropathies and musculoskeletal pain, but their use is limited because they are painful and inconvenient to apply, normally requiring multiple daily applications for only modest relief. Recently, a high concentration capsaicin patch has been developed (NGX-4010; NeurogesX, Inc.) that is believed to provide effective and sustained relief from pain.
The present invention provides additional methods and compositions for administration of capsaicin and other TRPV1 agonists.